Natural products are a rich source of novel organic compounds, many of which have interesting and desirable biological activities. From extracts of an organism of interest, such as marine invertebrates, methods of chemical separation and analysis may be applied to elucidate the structure of biologically active compounds. These chemical structures then form the basis for synthetic modifications to enhance the desired activity.
Marine ascidians, or sea squirts, have a number of unique secondary metabolites with potent biological activity. Colonial ascidians within the family Didemnidae have been particularly prolific, containing nitrogenous amino acid derived metabolites, including various cyclic peptides. The compounds termed didemnimides were isolated from Didemnum conchyliatum. These compounds are indole-maleimide-imidazole alkaloids, which could hypothetically be synthesized as a condensation of tryptophan and histidine
The further study of Didemna products, and the characterization of their active agents, is of particular interest for the development of novel therapeutic agents and uses thereof.
Relevant Literature
Didemnimide compounds are described by Vervoot et al. (1997) J. Org. Chem. 62:1486-1490. In describing synthesis of such didemnimide compounds, Terpin et al. (1998) Tetrahedron 54:1740-1752 reported a ring closing event that may occur upon irradiation or upon recrystallization from methanol of a Boc protected intermediate used in the didemnimide synthesis scheme.
Known G2 checkpoint inhibitors include purine analogues, e.g. caffeine, pentoxifylline, 2-aminopurine, 6-dimethylaminopurine; and staurosporine with its derivative UCN-01 (7-hydroxystaurosporine). See, for example, Busse et al. (1978) Radiat. Res. 76:292-307; Schlegel (1986) Science 232:1264-1266; Downes et al (1990) J. Cell. Biol. 110:1855-1859; Steinmann et al. (1991) P.N.A.S. 88:6843-6847; Andreasson et al. (1992) P.N.A.S. 89:2272-2276; Tam et al. (1992) Cell Growth Differ. 3:811-817; and Wang et al. 1996) J. Nat'l Cancer Inst. 88:956-965.
Experiments employing cells deficient in the tumour suppressor protein p53 have demonstrated the value of the two groups of G2 checkpoint inhibitors described above, for selectively sensitizing cancer cells. Pentoxifylline has been shown to enhance cisplatin induced killing of p53-MCF-7 cells 30-fold and radiation induced killing of p53-A549 human lung adenocarcinoma cells 5-fold. For example, see Russell et al. (1995) Cancer Res. 55:1639-1642; Powell et al. (1995) Cancer Res. 55:1643-1648; Russell et al. (1996) Int. J. Radiat. Oncol. Biol. Phys. 36:1099-1106; Yao et al. (1996) Nature Med. 2:1140-1143; and Bracey et al (1997) Clin. Cancer Res. 3:1371-1381.